The present invention relates to the use of melt extrusion technology in the production of bioavailable sustained-release matrix pharmaceutical formulations. Previously, melt extrusion has been used in the production of immediate release formulations.
It is known in the pharmaceutical art to prepare compositions which provide for controlled release of pharmacologically active substances contained in the compositions after oral administration to humans and animals. Such slow release compositions are used to delay absorption of a medicament until it has reached certain portions of the alimentary tract. Such sustained-release of a medicament in the alimentary tract further maintains a desired concentration of said medicament in the blood stream for a longer duration than would occur if conventional rapid release dosage forms are administered.
Different methods of preparing controlled release pharmaceutical dosage forms have been suggested. For example, direct compression techniques, wet granulation techniques, encapsulation techniques and the like have been proposed to deliver pharmaceutically active ingredients to the alimentary tract over extended periods.
Additionally, various types of sustained release formulations are known in the art, including specially coated pellets, coated tablets and capsules wherein the slow release of the active medicament is brought about through selective breakdown of the coating of the preparation or through compounding with a special matrix to affect the release of a drug. Some sustained release formulations provide for related sequential release of a single does of an active compound at predetermined periods after administration.
It is the intent of all sustained-release preparations to provide a longer period of pharmacologic response after the administration of the drug and is ordinarily experience after the administration of the rapid release dosage forms. Such longer periods of response provide for many inherent therapeutic benefits that are not achieved with corresponding short acting, immediate release preparations. This is especially true in the treatment of cancer patients or other patients in need of treatment for the alleviation of moderate to severe pain, where blood levels of an opioid analgesic medicament must be maintained at a therapeutically effective level to provide pain relief. Unless conventional rapid acting drug therapy is carefully administered at frequent intervals to maintain effective steady state blood levels of the drug, peaks and valleys in the blood level of the active drug occur because of the rapid absorption, systemic excretion of the compound and through metabolic inactivation, thereby producing special problems in maintenance of analgesic efficacy.
The prior art teaching of the preparation and use of compositions providing the sustained-release of an active compound from a carrier is basically concerned with the release of the active substance into the physiologic fluid of the alimentary tract. However, it is generally recognized that the mere presence of an active substance in the gastrointestinal fluids does not, by itself, insure bioavailability.
In order to be absorbed, the active drug substance must be in solution. The time required for a given proportion of an active substance from a unit dosage form is determined as the proportion of the amount of active drug substance released from a unit dosage form over a specified time base by a test method conducted under standardized conditions. The physiologic fluids of the gastrointestinal tract are the media for determining dissolution time. The present state of the art recognizes many satisfactory test procedures to measure dissolution time for pharmaceutical compositions, and these test procedures are described in official compendia world wide.
Although there are many diverse factors which influence the dissolution of drug substance from its carrier, the dissolution time determined for a pharmacologically active substance from the specific composition is relatively constant and reproducible. Among the different factors affecting the dissolution time are the surface area of the drug substance presented to the dissolution solvent medium, the pH of the solution, the solubility of the substance in the specific solvent medium, and the driving forces of the saturation concentration of dissolved materials in the solvent medium. Thus, the dissolution concentration of an active drug substance is dynamically modified in its steady state as components are removed from the dissolution medium through absorption across the tissue site. Under physiologic conditions, the saturation level of the dissolved materials is replenished from the dosage form reserve to maintain a relatively uniform and constant dissolution concentration in the solvent medium providing for a steady state absorption.
The transport across a tissue absorption site of the gastrointestinal tract is influenced by the Donnan osmotic equilibrium forces on both sides of the membrane since the direction of the driving force is the difference between the concentrations of active substance on either side of the membrane, i.e., the amount dissolved in the gastrointestinal fluids and the amount present in the blood. Since the blood levels are constantly being modified by dilution, circulatory changes, tissue storage, metabolic conversion and systemic excretion, the flow of active materials is directed from the gastrointestinal tract into the blood stream.
Notwithstanding the diverse factors influencing both dissolution and absorption of a drug substance, a strong correlation has been established between the in-vitro dissolution time determined for a dosage form and (in-vivo) bioavailability. The dissolution time and the bioavailability determined for a composition are two of the most significant fundamental characteristics for consideration when evaluating sustained-release compositions.
Melt granulation techniques have also been suggested to provide controlled release formulations. Generally, melt granulation involves mechanically working an active ingredient in particulate form with one or more suitable binders and/or pharmaceutically acceptable excipients in a mixer until one or more of the binders melts and adheres to the surface of the particulate, eventually building up granules.
U.S. Pat. No. 4,957,681 (Klimesch, et. al.) discloses a continuous process for preparing pharmaceutical mixtures having at least two components which are continuously metered. The process includes continuously metering the individual components of the pharmaceutical mixture at a rate of at least 50 g/h on electronic differential metering balances having a metering accuracy of at lest .+-.5% within time intervals of less than one minute and, additionally, having screw conveyors, thereby obtaining a substantially uniformly metered mixture, and shaping the mixture. Example 1 of the '681 patent is representative of the process. The requisite amounts of a copolymer having a K value of 30 and obtained from 60% of N-vinylpyrrolid-2-one (NVP), stearyl alcohol and theophylline are metered via three metering balances into the hopper of an extruder and extruded. The temperatures of the extruder cylinder consisting of six shots ranged from 30-60.degree. C. and the die is heated to 100.degree. C. The resultant extrudate is then pressed into tablets of the required shape. The '681 patent does not disclose preparation of sustained release opioid pharmaceutical formulations.
N. Follonier, et al., Hot-Melt Extruded Pellets for the Sustained Release of Highly Dosed Freely Soluble Drugs, Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 18 (1991) describes certain diltiazem hydrochloride formulations prepared using hot-melt screw-extrusion to obtain sustained-release pellets to be filled into hard gelatin capsules. The polymers used were ethylcellulose, a copolymer of ehtyl acrylate and methyl methacrylate containing quaternary ammonium groups, cellulose acetate butyrate, poly(vinyl chloride-co-vinyl acetate) and a copolymer of ethylene and vinyl acetate. In order to lower the extrusion temperature, some plasticizers were used.
WO 93/07859 described drug loaded pellets produced through melt spheronization wherein the therapeutically active agent is blended with various excipoients and binders; the formulation is fed to an extruder where it is heated and extruded at a speed of about 0.05 to 10 mm/sec. at approximately 60-180.degree. C. The extrudate is then cut into pieces in a pelletizer and subsequently fed to a spheronizer for uniform pellet formulation.
Despite the foregoing advances and the various techniques for preparing sustained release formulations available in the pharmaceutical art, there is a need in the art for an orally administrable opioid formulation which would provide an extended duration of effect which is also easy to prepare, e.g via melt-granulation techniques.